One of important factors causing brain cell damage is glutamate as an amino acid. Glutamate acts primarily through four types of receptors, such as NMDA (N-methyl-D-aspartate) receptor, AMPA (L-α-amino-3-hydroxyl-5-methyl-4-isoxazolpropionate) receptor, kainate receptor and 1S,3R-ACPD receptor [Craig C R, Stitzel R E, Modern Pharmacology with Clinical Applications, p293-302, 1997]. Under a stimulus such as cerebral ischemia, it reduces oxygen supply on neurons, and as a result increases anaerobic glycolysis, decreases action of ion pump by reducing ATP as an energy source within tissues, and induces depolarization of neuronal cell membranes by increasing the amount of extracellular potassium ion. In this state, it secretes excitatory neurotransmitter and induces brain damage due to activation of NMDA, AMPA and kainate receptors.
Excito-toxicity caused by excitatory neurotransmitter induces cell stresses, and is generally known that it plays an important role in inducing pathological state like neurodegenerative disorders, such as Alzheimer's disease, Parkinson disease, cerebral apoplexy and amyotrophic lateral sclerosis [Haloween, B., Reactive oxygen species and the central nervous system, J. Neurochem. 59, p1609-1623, 1992; Coyle, J. T. and Puttfarcken, P., Oxidative stress, glutamate, and neurodegenerative disorders, Science 262, p689-695, 1993; Olanow, C. W., A radical hypothesis for neurodegeneration, Trends Neurosci. 16, p439-444, 1993]. At times, neurodegenerative disorders in central nervous system accompany the decline of memory and cognitive functions. In particular, dementia, that is a serious problem in modern aging society, is caused by environmental factors such as inheritance, aging, brain damage, smoking and drinking habits, and other complex factors. Hippocampus is mainly damaged, and in general it is closely related to the reduction of acetylcholine content of the brain. At present, for the purpose of increasing acetylcholine content of the brain, acetylcholine esterase inhibitors are generally used for the treatment of Alzheimer's dementia. Besides, a large number of studies for inhibiting this brain damage are in progress [Gagliardi R J, Neuroprotection, excitotoxicity and NMDA antagonists, Arq. Neuro-Psiquiatr. P58, 2000], for example, the development of NMDA antagonist, AMPA antagonist, GABA agonist, intracellular calcium reducer, nitric oxide inhibitor, free radical scavenger, sodium channel inhibitor, glutamate free inhibitor, growth factor, acidosis, hypothermia, potassium channel activators, etc. have been tried.
For NMDA antagonists, dozocyilpin (MK 801), selfotel, cerestat, dextmetofan, etc. have been developed, however, a low dosage of these medicines induces changes in perceptual recognition, discomfort, nystagmus, etc., moreover, a high dosage of these shows mental side effects such as excitement, paranoia, illusion. Besides, NBQX has been developed for AMPA antagonist, however, it has a low possibility in practical use for medical treatment due to manifestation of serious nephrotoxicity.
Therefore, the development of brain protective agents having no toxicity is a matter of urgency.
According to recent studies, it has been disclosed that AMPA receptors play an important role in developing Alzheimer's disease since neuronal cell damage caused by activating the AMPA receptors selectively affects basal forebrain cholinergic neurons (BFCNs), which are related to Alzheimer's disease. It has been suggested that development of treatment strategies for Alzheimer's disease can be attempted with the use of AMPA antagonists. [Weiss, J. H. et al., Basal forebrain cholinergic neurons are selectively vulnerable to AMPA/kainate receptor-mediated neurotoxicity, Neuroscience 60, p659-664]. Glial cell plays a decisive role in the survival of neurons. In central nervous system under being developed, the glial cell controls precise movement and proliferation of neurons, and after development it takes part in maintaining homeostasis and synaptic plasticity of neurons. Moreover, glial cell contains receptors and neurotransmitters, which can start the message of neurons that is essential for survival and extinction of neurons. As a result, therefore, protecting glial cell from exterior damages is related to plasticity, homeostasis and survival.
Pericarpium zanthoxyli refers to the rind of dried fruits of zanthoxylum bungeanum Maxim., zanthoxylum schinifolium Sieb. Et Zucc., and zanthoxylum piperitum A. P. DC, which are distributed in Korea, China, etc., for the ingredient it contains (+)-gamma-cadinene, (+)-beta-pinene, (−)-aromadendrene, (−)-isopulegol, (−)-N-acetylanonaine (R-type), (2E, 4E, 8Z, 11E)-2-hydroxy-N-isobutyl-2,4,8,11-tetradecatetraenamide, (2E, 4E, 8Z, 11Z)-2-hydroxy-N-isobutyl-2,4,8,11-tetradecatetraenamide, (2E, 4E, 8E, 10E, 12E)-2-hydroxy-N-isobutyl-2,4,8,10,12-tetradecatetraenamide, 2-trans-6-trans-8-trans-10-trans-2-hydroxy-N-isobutyldodeca-2,6,8,10-tetradecatetraenamide, 1,8-cineole, 2-phenylpropane-2-ol, arnottianamide, citronellal, de-N-methylcholerythrine, halopine, hydroxy-α-sanshool, hydroxy-β-sanshool, hydroxy-γ-sanshool, linalool, nerol, piperitone, skimmianine, terpinen-4-ol, zanthoxylin, zanthobungeanine, α-pinene, (+,−)α-sanshool, α-terpineol, α-thujene, β-sanshool, β-sitosterol, γ-sanshool, trans-ocimene, etc. It has been used for cold perspiration in spleen and stomach, cold and painful stomach, diarrhea, chilly waist and knee, indigestion, acute and chronic gastritis, dysentery, toothache, etc. and generally known for antiparasitic and antibacterial effect. [Cheong, Bo-seop and Shin, Min-gyo, Iconographical Folk Medicine Encyclopedia, Younglim Co., Ltd. P795-796, 1999; New Oriental Medicine Handbook, Traditional Oriental Medicine Database, Scientific Research Center of Natural Substances, Seoul University, 1999].
Until now, however, there is no report that pericarpium zanthoxyli has an effect of protecting brain cells and improving memory.
The inventors of the present invention have studied for a long time on the materials for inducing an effect of protecting brain cells and improving memory for modern people under brain damage that is caused by environmental factors, such as various stresses, drinking and smoking habits, and have eventually discovered that pericarpium zanthoxyli shows an effect of protecting brain cells and improving memory to complete the present invention. It is an object of the invention to provide pharmaceutical compositions and health supplements showing an effect of protecting brain cells and improving memory.